Abstract

The pentapeptide repeat protein (PRP) family has more than 500 members in the prokaryotic and eukaryotic kingdoms. These proteins are composed of, or contain domains composed of, tandemly repeated amino acid sequences with a consensus sequence of [S,T,A,V][D,N][L,F][S,T,R][G]. The biochemical function of the vast majority of PRP family members is unknown. The three-dimensional structure of the first member of the PRP family was determined for the fluoroquinolone resistance protein (MfpA) from Mycobacterium tuberculosis. The structure revealed that the pentapeptide repeats encode the folding of a novel right-handed quadrilateral beta-helix. MfpA binds to DNA gyrase and inhibits its activity. The rod-shaped, dimeric protein exhibits remarkable similarity in size, shape, and electrostatics to DNA.

Fluoroquinolones are synthetic derivatives of nalidixic acid and exhibit broad-spectrum and powerful antibacterial activity (). Prior to 1998, all mechanisms of bacterial fluoroquinolone resistance had been shown to be either due to a) mutations in the type II topoisomerases, DNA gyrase and topoisomerase IV, that are the targets of these drugs or b) increased expression of efflux pumps that reduce the intracellular concentration of the drug. Neither of these resistance mechanisms has been shown to be transmissible between organisms. Therefore, the discovery of a plasmid-mediated, transmissible form of fluoroquinolone resistance in 1998 heralded a significant clinical concern. The 218 residue long QnrA protein was originally found on a conjugative plasmid isolated from a fluoroquinolone resistant strain of Klebsiella pneumoniae in Alabama (). Since then it has been found on transferable plasmids from fluoroquinolone resistant strains of K. pneumoniae isolated in 6 different states in the United States (). Outside of the United States, qnr genes have been found on plasmids in fluoroquinolone resistant isolates of Enterobacteriae from China (), Hong Kong (), Korea (), France (), Germany () and Egypt (). In some cases, the qnr genes were adjacent to genes that confer resistance to other antibiotics, such as sulfamethoxazole and the extended spectrum β-lactam antibiotics within Type I integrons that were apparently mobile, as they were found on an assortment of conjugative plasmids (, ). Thus, although several studies have found qnr genes in a small percentage of fluoroquinolone resistant strains in the United States (8 of 72; ) and Europe, it appears that the qnrA gene is present worldwide on integrons that can integrate into a series of promiscuous plasmids within many species of Enterobacteriaceae.